Improved method of separating



Patented Apr. 19, 1938 UNITED STATES PATENT FFlCE IMPROVED METHOD OFSEPARATING MIXED ERGOT ALKALOIDS Willy Heinrich Kuessner, Darmstadt,Germany, assignor to Merck & Co. Inc., Rahway, N. J., a corporation ofNew Jersey 4 Claims.

This is a division of application Serial Number 731,464, filed June 20,1934.

The present invention relates broadly to improvements in the method ofseparating mixed ergot alkaloids, and more particularly it is concernedwith the production of a new ergot alkaloid.

According to the process of Berger and Carr, [JOLHIL of the ChemicalSociety, London, vol. 91 (1907) pp. 337-353], aqueous solutions of saltsof the combined ergot alkaloids are mixed with caustic alkalies and theliberated ergotinine extracted with organic solvents, after which theaqueous lye is neutralized, realkalized with sodium carbonate, andshaken out with ether. The residue of the ethereal solution isrecrystallized as the phosphate from 80% alcohol. Bargers end productwas therefore crystallized ergotoxine phosphate. It was noticed thatwith the process of Barger and Carr, the ergotoxine phosphatecrystallizes out of the phosphoric-acid-alcoholic solution only afterstanding for a protracted period. Furthermore, a resinous substance isfreed which renders separation of the ergotoxine crystals very difiicultand requires further wasteful, repeated solutions.

By the present process, I have found that better yields of ergotoxine,in purer form, can be obtained by acidifying the caustic-alkaline aque-30 ous solution (which has been freed from ergotinine), and thenextracting, in the acid state, with an organic solvent. Lactic acid wasfound particularly suitable for acidulation of the caustic-alkalineaqueous solution, but the following 35 acids have also been employedsuccessfullyacetic, tartaric, hydrochloric, sulphosphoric, andphosphoric. The organic solvents, used in this extraction process may bethe ordinary solvents used for the preparation of ergotoxine, but ether40 is preferable. The ergotoxine is found in the ethereal extract, andcan be easily obtained by permitting it to crystallize out afterevaporation. If desired, it may first be transformed into a salt.

By the process herein disclosed, the salts of ergotoxine crystallize outwithin a few hours and are free from resinous secretions such as areobtained in the preparation of ergotoxine phosphate according to theBarger and Carr process, as already pointed out. The ergotoxine phos- 0phate, for instance, is obtained in the form of nearly-white well-formedcrystals having a melting point of 170-171. In order to obtain a productof similar purity by the Barger and Carr process it is necessary tore-dissolve the ergotoxine phosphate several times, and this causes theyield to fall considerably below that obtained by A my process.

Furthermore, according to my invention, the first extraction of thecaustic-alkaline solution of the complete extract contains principallyergotinine, besides substantial quantities of ergotoxine. The formercrystallizes out of the evaporation residue. The mother liquorscontaining the ergotoxine may advantageously be added to the solution tobe acidulated, from which the ergotoxine is obtained.

After extraction of the ergotoxine according to my above-describedprocess, I found that a hitherto unknown alkaloid remained in theacidulated aqueous solution. According to my method, this new alkaloidis obtained by alkalizing the acidulated aqueous solution, from whichthe ergotoxine has been produced, with alkali metal carbonates such as,for instance, sodium carbonate or bicarbonate, and thereafter extractingwith suitable organic solvents. For this latter step of the process,organic solvents as possess a high degree of solvency should bepreferably used, for example, chlorinated hydrocarbons-chloroform,dichloroethylene, trichlorethylene-are suitable. Ordinarily, the newalkaloid crystallizes out immediately from the residue of the organicsolvent used in the extraction after concentration of the solution. Itis then further refined by recrystallization, preferably from aqueousalcohol or trichlorethylene. The new alkaloid can thus be obtained in ayield of approximately 20% of the combined alkaloids employed.

In general, then, the new alkaloid is obtained by removing from thecombined alkaloid mixture prepared from ergot in the usual manner, allingredients slightly soluble in caustic-alkalized or acidulated aqueoussolutions by extracting with organic solvents, mixing the remainingaqueous solution with alkali carbonates, and thereafter treating thesolution in the manner hereinbefore described.

This new alkaloid is highly active physiologically, and has been foundto be as effective as the highly active alkaloid known as ergotamine. Itmelts at 170-121 when dried to weight constancy over phosphoruspentoxideat 20 C. and about 20 mm. pressure. In 1% chloroform solution it isdeXtro-rotary Thus dried and in finely ground form, it liberates stillmore water when heated for several hours to 80 over phosphorus pentoxideat 1-2 mm. pressure under tumorescence. The completely dehydrated, veryhygroscopic product has a melting point of I'm-178 and the rotation (1%in chloroform). The crystallized new alkaloid has the approximateformula C31H3'7N505H20.

The above characteristics distinguish my new product from alkaloidsalready known, such as ergotamine ergotaminine, ergotoxine, ergotinine,and Sensibamin. It is particularly distinguished from the alkaloidSensibamin which is described in British Patent No. 388,529. WhileSensibamin is unstable in alcohol, ether, acetone, and the like, my newalkaloid may be recrystallized from these solvents without changing itsproperties. For instance, ethanol (96%) dissolves the new alkaloid at 20in a proportion of 1:33; when the ethanol is at boiling temperature theproportion is 1:6.

The various steps of my process are set forth in the accompanyingexamples. Obviously, these steps may be modified considerably withrespect to their order and number and the specific materials used,without departing from the spirit of the invention substantially asdescribed and claimed, and it is understood that I do not desire tolimit myself to the specific embodiments shown.

Example 1000 gms. of 1% aqueous solution of salts of the combined ergotalkaloids, obtained by the usual method, are mixed with 30 gms. causticsoda (specific gravity 1.34) and thereafter extracted with 500, 250, and250 cc. benzol, respectively. The benzol solution is evaporated and fromit the ergotinine (30 to 50% of the combined alkaloids, depending uponthe source) is obtained by crystallizing out and recrystallization. Themother liquids of the ergotinine production are mixed with thecaustic-alkaline-aqueous alkaloid solution and the latter acidulatedwith 30 gms. lactic acid (specific gravity 1.16). This. acid solution isextracted with 400, 200, and 200 cc. benzol, respectively, and from thebenzol, the ergotoxine (-20% of the combined alkaloids) is obtained asthe phosphate, by evaporation, after treating with diluted alcoholicsolution of phosphoric acid, permitting it to crystallize out, andsubsequently reorystallizing it. The acidulated, aqueous alkaloidsolution is weakly alkalized with sodium carbonate and extracted with200, 100, and 100 cc. of benzol, respectively; the dried benzol solutionis concentrated in vacuo to 50 cc. and left standing for 12-24 hours ina cool, dark place, whereupon the newly crystallized alkaloid isfiltered off by suction. This is recrystallized to a constant meltingpoint, for instance, from the ten-fold quantity of benzol.

I claim:

1. A process for the separation of certain ergot alkaloids whichcomprises mixing aqueous solutions of salts of the combined ergotalkaloids with caustic soda, shaking the mixture with benzol, freeingthe alkaloid ergotinine, mixing the liquors of the crgotinine productionwith the caustic-alkaline-aqueous alkaloid solution, acidulating themixture, shaking with benzol, freeing ergotoxine, alkalizing theacidulated aqueous alkaloid solution, extracting this last-namedsolution with benzol, evaporating the solvent to crystallize out the newalkaloid, and recrystallizing the same to constant melting point.

2. A process for the production of ergotoxine from an aqueous solutionof a mixture of salts of combined ergot alkaloids which has previouslybeen free from ergotinine, which comprises combining the mother liquorof the ergotinine production with the aqueous alkaloidal solution,acidulating the combined solutions, extracting with benzol, treating theextraction product with an acid, and evaporating the solvent tocrystallize out ergotoxine in the form of its corresponding salt.

3. A process for the production of a new ergot alkaloid from an aqueoussolution of a mixture of salts of combined ergot alkaloids which hasbeen previously, substantially freed from ergotinine and ergotoxinewhich comprises alkalizing the acidulated aqueous residual alkaloidalsolution remaining after such extraction, extracting the alkalizedsolution with benzol, and evaporating the solvent.

4. A process for the separation of certain ergot alkaloids whichcomprises alkalizing an aqueous solution of salts of combined ergotalkaloids, extracting with benzol, freeing the alkaloid ergotinine,mixing the liquors of the ergotinine production with the alkalizedaqueous alkaloid solution, acidulating the mixture, extracting withbenzol, freeing ergotoxine, alkalizing the acidulated aqueous alkaloidsolution, extracting with benzol, and evaporating the solvent.

WILLY HEINRICH KUESSNER.

